eBulletin Newsletter

NCCN Flash Updates: NCCN Guidelines Updated for Neuroendocrine and Adrenal Tumors

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Radiation Therapy Compendium™, the NCCN Drugs & Biologics Compendium (NCCN Compendium^®), and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Neuroendocrine and Adrenal Tumors. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Neuroendocrine and Adrenal Tumors 

Global

• Terms bronchopulmonary and bronchial have been revised to lung.
• Term debulking has been revised to cytoreduction.
• Term Primary Treatment has been revised to First-Line Treatment.

Clinical Presentations and Diagnosis

CP-1

• Third heading revised: Neuroendocrine Tumors Neoplasms of Unknown Primary (Well-Differentiated Grade 1/2) (NUP-1)
• Footnote removed: For well-differentiated grade 3 NET, see WDG3-1. For poorly differentiated/large or small cell carcinomas, see PDNEC-1.

Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Differentiated Grade 1/2), Lung and Thymus

NET-1

• Footnote c revised: SSTR-PET/CT or SSTR-PET/MRI of skull base vertex to mid-thigh with multiphase IV contrast when possible. . . (Also pages NET-2 through NET-4, NET-5A, NET-6, NET-7 and NET-9)
• New footnotes added:
  • Footnote b: Multiphasic imaging studies are performed with intravenous (IV) contrast in arterial and portal venous phases. (Also pages NET-2 through NET- 4, NET-5A, NET-6 through NET-9, NET-12, and NET-14)
  • Footnote e: SSTR-PET/CT or SSTR-PET/MRI should not be used to limit the extent of lymphadenectomy or small bowel resection as sensitivity may not be adequate.
• Footnotes removed and added as links in the algorithm:
  • Principles of Imaging. (Also pages NET-2 through NET-4, NET-5A, NET-6 through NET-9, NET-13, and NET-14)
  • Principles of Biochemical Testing. (Also pages NET-2, NET-4, and NET-5A through NET-9)
  • Principles of Surgical Management of Neuroendocrine Tumors. (Also pages NET-2, NET-5A through NET-7, and NET-9)

NET-2

• Surveillance, top option following Noninvasive tumors revised: Routine eEndoscopic surveillance every 3-12 mo for the first y and then annually thereafter.

NET-3

• New second column added: First-Line Treatment
  • Following Appendix, Simple appendectomy added.
    • Following Simple Appendectomy:
      • Top pathway revised: Tumor ≤2 <1 cm
        • Removed from pathway: Simple appendectomy
      • New pathway added: Tumor ≥1 to ≤2 cm
        • Added to Surveillance column: Optional surveillance every 2-5 y based on clinical pathologic features.
• Heading for fifth column revised: Primary Additional Treatment

NET-3 (continued)

• Footnote k revised: See Staging (ST-6). Patients with tumors <2 cm that do not invade beyond the mesoappendix can be considered for observation, after patient-physician discussion. Heller DR, et al. J Am Coll Surg 2019;228:839-851. Some NCCN member institutions Consideration for consider right hemicolectomy can be made for 1- to 2-cm tumors with poor prognostic features. See Discussion for details.
• New footnote l added: Ahmed FA, et al. Surgery 2024;175:251-257. Nesti C, et al. Lancet Oncol 2023;24:187-194.

NET-4

• Bottom of page following T2-T4, As appropriate, new bullet added: Biochemical evaluation as clinically indicated (NE-E).

NET-5

• Evaluation column, new bullet added: Biochemical evaluation as clinically indicated (NE-E).
• Following the Evaluation column, new pathway added: Other
• Primary First-Line Treatment/Surveillance column:
  • Top option revised: Endoscopic resection of prominent >1 cm gastric tumors (NE-F).
  • Following Hyper-gastrinemic/Type 2. . .:
    • Removed all subsequent recommendations and added Endoscopic resection of >1 cm gastric tumors (NE-F) and See gastrinoma (PanNET-3) for identification and treatment of the gastrin-producing tumor.
• New column header added to far right of page: Surveillance
  • Top pathway revised: Every 2-3 y or clinically indicated: Endoscopic surveillance EGD at 1 year and endoscopic resection of prominent tumors then every 1-3 y thereafter.
  • Middle pathway, added: EGD at 1 y and then clinically indicated as needed.

NET-5A

• New footnote u added: There is increasing evidence that patients who have been on long term PPI therapy may be at an increased risk of developing gastric NETs (gNETs), which appear to have a much lower propensity to metastasize than sporadic type 3 tumors.
• Footnote removed and added as a link in the algorithm: Principles of Hereditary Cancer Risk Assessment and Genetic Counseling. (Also pages NET-6 and NET-7)
• Footnotes removed:
  • For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. Higher doses have been shown to be safe. For breakthrough symptoms, octreotide 100–250 mcg SC TID can be considered.
  • If injection site-related complications occur, consider switching to another SSA.

NET-6

• New column header added to far right of page: Surveillance.
• Footnote removed and added as a link in the algorithm: Principles of Systemic Anti-Tumor Therapy. (Also pages NET-9, NET-10, NET-12, and NET-14)

NET-7

• New column header added to far right of page: Surveillance.

NET-8

• Surveillance column:
  • 12 wk-12 mo post-resection:
    • Third bullet revised: Multiphasic abdominalen ± pelvics CT or MRI for primary GI NETs and PanNETs (as clinically indicated for lung and thymic NETs) (NE-D).
    • Fourth bullet revised: Chest/abdomen CT ± with contrast for primary lung/thymus tumors thymic NETs (as clinically indicated for primary GI tumors).
  • >1 y post-resection to 10y:
    • Third sub-bullet revised: Multiphasic abdominalen ± pelvics CT or MRI for primary GI NETs and PanNETs (as clinically indicated for lung and thymic NETs) (NE-D).
    • Fourth sub-bullet revised: Chest/abdomen CT ± with contrast for primary lung/thymus tumors thymic NETs (as clinically indicated for primary GI tumors).

NET-9

• Following Evaluation column:
  • Top pathway revised: If surgical debulking cytoreduction of metastases possible (NE-F).
  • New pathway added: If surgical cytoreduction of metastases not possible.
    • Top pathway revised: Unresectable, lLow tumor burden.
    • Bottom pathway revised: Unresectable, cClinically significant tumor burden.
    • Pathway removed: Unresectable, locally symptomatic from primary tumor.
• Treatment column:
  • Top pathway revised: Resect primary, regional lymph nodes + metastases (NE-F).
  • Second pathway revised: Consider resection of primary tumor, particularly if symptomatic (NE-F) and/or Observe with imaging or octreotide long-acting release (LAR) or lanreotide.
  • Bottom pathway revised: Consider resection of primary tumor, particularly if symptomatic (NE-F) and/or Octreotide LAR or lanreotide (NE-H 1 of 9) and/or Aalternative front-line therapy (see options for disease progression [NET-10 and NE-H 1 of 9])
• Far right column revised: Clinically or Radiologically Significant Disease Progression (NET-10).
• Footnotes revised:
  • Footnote ff: Primary + regional lymph node Rresection should be considered to reduce further obstruction, mesenteric ischemia, bleeding, or perforation.
  • Footnote jj: In select cases, it may be appropriate to proceed to front-line systemic therapy or liver-directed locoregional therapy prior to or concurrently with octreotide LAR or lanreotide.
• Footnote removed: Noncurative debulking cytoreduction surgery might be considered in select cases.

NET-10

• First column revised: Clinically or radiologically Significant Disease Progression.
• Subsequent Therapy column: Options under Systemic therapy were removed and a link to NE-H 1 of 9 was added.
• Footnote kk revised: If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-functional tumors and continued in patients with functional tumors; these regimens may be used in combination with any of the subsequent options. For details on the administration of octreotide LAR or lanreotide with lutetium Lu 177 dotatate, see NE-J. (Also pages NET-11, NET-12, and NET-14)
• Footnotes removed and added as a link in the algorithm:
  • Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases. (Also NET-12)
  • Principles of Radiation Therapy.
• Footnotes removed:
  • After clinical, symptomatic, or radiographic progression on standard SSA doses, for symptom and/or tumor control, above-label dosing octreotide LAR (up to 60 mg once a month) or lanreotide (up to 120 mg every 14 days) may be useful in select cases. (Also NET-12)
  • Principles of Peptide Receptor Radionuclide Therapy with Lutetium Lu 177 Dotatate (NE-H). (Also page NET-12)

NET-11

• Footnote ll revised: For symptom control, consider addition of focal therapy (ie eg, endobronchial therapy debulking, ablation). (Also page NET-12)
• New footnote mm added: Phase III study done in non-functional tumors.
• Footnote removed and added as a link in the algorithm: Principles of Peptide Receptor Radionuclide Therapy with Lutetium Lu 177 Dotatate.

NET-12

• Top header revised: Management of Distant Metastases (Bronchopulmonary Lung or Thymus) or Multiple Lung Nodules or Tumorlets and Evidence of DIPNECH.
• Primary First-Line Therapy column, second pathway: Removed all systemic therapy recommendations and revised to Systemic therapy options (NE-H 2 of 9).
• Bottom pathway moved to NET-13: Multiple lung nodules or tumorlets and evidence of DIPNECH.
• Footnote oo revised: Observation can be considered in select patients with low burden of disease and favorable prognostic features if asymptomatic or for tumors on the lower end of the spectrum.
• Footnote removed: Cisplatin + etoposide, carboplatin + etoposide, or temozolomide ± capecitabine can be considered for intermediate-grade/atypical tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum.

NET-13

• New column header added to far right of page: Surveillance.
• Primary First-Line Therapy column, options revised: Observe or A trial of octreotide LAR or lanreotide for symptom control (if chronic cough/dyspnea is not responsive to inhalers or conventional treatment).
• Footnotes revised:
  • Footnote gg: For symptom and/or tumor control, octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. Higher doses have been shown to be safe. For breakthrough symptoms, octreotide 100–250 mcg SC TID can be considered.
  • Footnote rr: Almquist D, et al. J Clin Oncol 2019;37:Abstract e20029. Al-Toubah T, et al. Chest 2020;158:401-405.

NET-14

• Evaluation column, bullets revised:
  • First bullet: Routine Bbiochemical evaluation with 24-hour urine or plasma 5-HIAA (NE-E).
  • Second bullet: Baseline Eechocardiogram.
• Surveillance column, first bullet revised: Echocardiogram every 1–3 y or as clinically indicated for patients without carcinoid heart disease (CHD) and at least annually for patients with established CHD (NE-D).

Neuroendocrine Tumors of the Pancreas (Well-Differentiated Grade 1/2)

PanNET-1

• Footnotes revised:
  • Footnote a: Principles of Pathology for the Diagnosis and Reporting of Neuroendocrine Tumors Neoplasms (NE-A). (Also pages PanNET-3, PanNET-5, PanNET-7, and PanNET-9)
  • Footnote c: SSTR-PET/CT or SSTR-PET/MRI of skull base vertex to mid-thigh with multiphase IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs. (Also pages PanNET-3, PanNET-5, PanNET-7, PanNET-9, and PanNET-12A)
• New footnote b added: Multiphasic imaging studies are performed with IV contrast in arterial and portal venous phases. (Also pages PanNET-3, PanNET-5, PanNET-7, PanNET-9, PanNET-11, and PanNET-12A)
• Footnotes removed and added as links in the algorithm:
  • Principles of Imaging.(Also pages PanNET-3, PanNET-5, PanNET-7, PanNET-9, PanNET-11, and PanNET-12A)
  • Principles of Hereditary Cancer Risk Assessment and Genetic Counseling.(Also pages PanNET-3, PanNET-5, PanNET-7, and PanNET-9)

PanNET-2

• Pathways following Resectable:
  • Following Small (≤2 1 cm), Treatment options revised: Observation in select cases or Enucleation ± regional lymphadenectomy or Pancreatectomy ± regional lymphadenectomy.
  • New pathway added: >1 to ≤2 cm
    • Following 1-2 cm, treatment options added: Observation in select cases or Pancreatectomy (NE-F) or Enucleation in select cases (NE-F).
  • Following Larger (>2 cm), invasive, or node-positive tumors revised:
    • Branches to Head and Distal removed.
      • Treatment options following Distal removed: Distal pancreatectomy + splenectomy + regional lymphadenectomy.
    • Single branch pathway revised: Pancreatoduodenectomy + regional lymphadenectomy (NE-F).
• Footnote removed and added as a link in the algorithm: Principles of Surgical Management of Neuroendocrine Tumors. (Also pages PanNET-4, PanNET-6, PanNET-8, PanNET-10, and PanNET-12A)

PanNET-3

• Footnote j revised: Serum gastrin can be falsely elevated with PPI use. To confirm diagnosis, it should ideally be checked when fasting and off PPI for >1 week. However, PPI or H2 blocker should be continued in patients with overt clinical symptoms of gastrinoma and/or risks of complications.
• Footnotes removed and added as links in the algorithm:
  • Principles of Biochemical Testing. (Also pages PanNET-5, PanNET-7, PanNET-9, PanNET-11, and PanNET-12A)
  • Principles of Hormone Control. (Also pages PanNET-4 through PanNET-10)

PanNET-4

• New column header added to far right of page: Surveillance. (Also pages PanNET-6, PanNET-8, PanNET-10, and PanNET-12)
• Pathway following Resectable:
  • Following Head:
    • First pathway removed: Exophytic or peripheral tumors by imaging.
      • Treatment options removed: Enucleation of tumor + periduodenal node dissection.
    • Second pathway removed: Deeper or invasive tumors and those in proximity to the main pancreatic duct.
    • Single branch pathway added: Pancreatoduodenectomy (NE-F).
• Footnote removed: Not adjacent to the main pancreatic duct.

PanNET-5

• Evaluation column, Recommended, new bullet added: Fasting blood glucose.

PanNET-12

• Following Evaluation column, top pathway revised: If complete resection cytoreduction possible (NE-F).
• Treatment column, bottom pathway: Second bullet revised: Consider oOctreotide LAR or lanreotide (if not already receiving) (NE-H 3 of 9).
• Footnotes revised:
  • Footnote z: If clinically significant disease progression, treatment with octreotide LAR or lanreotide should be discontinued for non-functional tumors and continued in patients with functional tumors; these regimens may be used in combination with any of the subsequent options. For details on the administration of octreotide LAR or lanreotide with lutetium Lu 177 dotatate, see NE-J. (Also page PanNET-13)
  • Footnote dd: In select cases, it may be appropriate to proceed to front-line systemic therapy or liver-directed locoregional therapy prior to or concurrently with octreotide LAR or lanreotide.
• Footnote removed and added as a link in the algorithm: Principles of Systemic Anti-Tumor Therapy. (Also page PanNET-13)
• Footnote removed: Noncurative debulking cytoreduction surgery might be considered in select cases.

PanNET-13

• Subsequent Therapy column, removed all systemic therapy recommendations and revised to: Clinical trial or Systemic therapy options (NE-H 3 of 9).
• Footnotes removed and added as links in the algorithm:
  • Principles of Radiation Therapy.
  • Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases.
• Footnotes removed:
  • Principles of Peptide Receptor Radionuclide Therapy with Lutetium Lu 177 Dotatate (NE-H).
  • After clinical, symptomatic, or radiographic progression on standard SSA doses, for symptom and/or tumor control, above-label dosing octreotide LAR (up to 60 mg once a month) or lanreotide (up to 120 mg every 14 days) may be useful in select cases.
  • Data for the use of belzutifan for larger tumors, locally advanced unresectable tumors, and distant disease are extremely limited. Clinical trials are ongoing.
  • The study excluded patients with prior systemic anticancer therapy, including anti-vascular endothelial growth factor therapy, patients needing immediate surgical intervention for tumor treatment, or patients with evidence of metastatic disease on screening imaging. Jonasch E, et al. N Engl J Med 2021;385:2036-2046.

Neuroendocrine Tumors Neoplasms of Unknown Primary

NUP-1

• First column revised: Biopsy-proven NETs Neuroendocrine Neoplasms of unknown primary.
• Initial Workup:
  • First bullet revised: Tumor-directed localizing studies.
  • New bullet added: Biochemical testing as appropriate (NE-E).
• New footnote d added: Multiphasic imaging studies are performed with IV contrast in arterial and portal venous phases
• Footnote e revised: SSTR-PET/CT or SSTR-PET/MRI of skull base vertex to mid-thigh with multiphase IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.
• Footnotes removed and added as links in the algorithm:
  • Principles of Imaging.
  • Principles of Biochemical Testing.

Well-Differentiated, Grade 3 Neuroendocrine Tumors

WDG3-1

• Evaluation column, Recommended, fourth bullet revised: SSTR-PET/CT or SSTR-PET/MRI (in patients with tumors Ki ≤55%) (NE-D).
• Footnotes revised:
  • Footnote c: SSTR-PET/CT or SSTR-PET/MRI of skull base vertex to mid-thigh with multiphase IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.
  • Footnote e: Consider both FDG-PET and DOTATATE-PET if considering PRRT.
  • Footnote f: Tumor/somatic molecular profiling should be considered for patients with locoregional unresectable/metastatic disease who are candidates for anticancer therapy to identify actionable alterations. . .
• New footnotes added:
  • Footnote a: Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Neoplasms (NE-A).
  • Footnote b: Multiphasic imaging studies are performed with IV contrast in arterial and portal venous phases. (Also pages WDG3-2 through WDG3-4)
• Footnotes removed and added as links in the algorithm:
  • Principles of Imaging. (Also pages WDG3-2 through WDG3-4)
  • Principles of Hereditary Cancer Risk Assessment and Genetic Counseling.

WDG3-2

• Treatment column: Removed options for neoadjuvant chemotherapy and added a link to NE-H 4 of 9.
• Footnote removed and added as a link in the algorithm: Principles of Systemic Anti-Tumor Therapy. (Also pages WDG3-3 and WDG3-4)
• Footnote removed: Temozolomide ± capecitabine may have more activity in tumors arising in the pancreas compared to GI NETs. (Also pages WDG3-3 and WDG3-4)

WDG3-3

• Treatment column:
  • Following Clinically significant tumor burden or evidence of disease progression:
    • All systemic therapy recommendations were removed and revised to: Clinical trial or Systemic therapy options (NE-H 4 of 9).
    • Locoregional therapy options, second bullet revised: Palliative RT for oligometastatic tumors disease and/or symptomatic metastases (excluding mesenteric masses).
  • Following Asymptomatic, low tumor burden, revised: Observation with short-interval follow-up scan, in selected patients or Octreotide LAR or lanreotide (if SSTR-positive and/or hormonal symptoms) or Palliative RT for oligometastatic tumors disease and/or symptomatic metastases (excluding mesenteric masses).
• New footnote i added: Krug S, et al. BMC Cancer 2019;19:362. (Also page WDG3-4)
• Footnotes removed and added as links in the algorithm:
  • Principles of Radiation Therapy. (Also page WDG3-4)
  • Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases.
• Footnotes removed:
  • After clinical, symptomatic, or radiographic progression on standard SSA doses, for symptom and/or tumor control, above-label dosing octreotide LAR (up to 60 mg once a month) or lanreotide (up to 120 mg every 14 days) may be useful in select cases.
  • Pembrolizumab can be considered for patients with microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR), or advanced tumor mutational burden-high (TMB-H) tumors (as determined by an FDA-approved test) that have progressed following prior treatment and have no satisfactory alternative treatment options. (Also page WDG3-4)
  • Consider trial of SSA before PRRT. Preliminary data suggest reduced efficacy if high Ki-67 and/or FDG-PET avid. See Principles of Peptide Receptor Radionuclide Therapy with Lutetium Lu 177 Dotatate (NE-H).

WDG3-4

• Treatment column, removed all systemic therapy recommendations and revised to: Clinical trial or Systemic therapy options (NE-H 4 of 9).
• Footnote m revised: Consider liver-directed therapy in selected cases with residual liver-predominant disease after systemic therapy. See Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases (NE-I).
• Footnote removed and added as a link in the algorithm: Principles of Biochemical Testing.

Extrapulmonary Poorly Differentiated: Neuroendocrine Carcinoma/Large or Small Cell Carcinoma/Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm

PDNEC-1

• Evaluation column, Recommended, first bullet revised: Multiphasic Cchest/abdominalen/pelvics CT (NE-D) or

PDNEC-1A

• Footnotes added:
  • Footnote a: Eads JR, et al. Endocr Relat Cancer 2023;30:e220206.
  • Footnote b: Sorbye H, et al. J Neuroendocrinol 2023;35:e13249.
  • Footnote f: Multiphasic imaging studies are performed with IV contrast in arterial and portal venous phases.

PDNEC-1A (continued)

• Footnotes revised:
  • Footnote e: Somatostatin scintigraphy SSTR-based imaging (SSTR-PET/CT or SSTR-PET/MRI) with single-photon emission computed tomography (SPECT)/CT is not part of the routine evaluation of PDNECs, but may be considered for morphologically well-differentiated tumors with higher proliferation index, as appropriate. See Principles of Imaging (NE-B).
  • Footnote g: Tumor/somatic molecular profiling should be considered for patients with locoregional unresectable/metastatic disease who are candidates for anticancer therapy to identify actionable alterations. . .
• Footnotes removed and added as links in the algorithm:
  • Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors.
  • Principles of Surgical Management of Neuroendocrine Tumors.
  • Principles of Systemic Anti-Tumor Therapy.
  • Principles of Radiation Therapy.

Adrenal Gland Tumors

AGT-1

• Evaluation column following Morphologic evaluation, Adrenal protocol, new tertiary bullet added: Consider additional imaging.
• Footnote a revised: Principles of Pathology for the Diagnosis and Reporting of Neuroendocrine Tumors Adrenocortical Carcinoma (NE-AB).
• New footnotes added:
  • Footnote b: If HU < +10, no PCC screening is needed.
  • Footnote c: Depending on HU and imaging characteristics, additional imaging and workup may be indicated. Fassnacht M, et al. Eur J Endocrinol 2023;189:G1-G42.
• Footnote removed and added as a link to the algorithm: Principles of Biochemical Testing. (Also pages AGT-2 and AGT-4)
• Footnotes removed:
  • For benign-appearing lesions, refer to the following guidelines for the management of adrenal incidentalomas: Zeiger MA, et al. Endoc Pract 2009;15 Suppl 1:1-20; Fassnacht M, et al. Eur J Endocrinol 2016;175:G1-G34.
  • If unenhanced is < +10 HU, then the tumor is probably benign. If unenhanced is > +10 HU, then use enhanced and washout. If >60% absolute washout in 15 minutes, the tumor is likely to be benign; if <60%, the tumor is possibly malignant (Caoili EM, et al. Radiology 2002;222:629-633). (Also page AGT-3)
  • For benign-appearing lesions, refer to the Endocrine Society's Clinical Practice Guidelines for the Treatment of Cushing's Syndrome (Fleseriu M, et al. Lancet Diabetes Endocrinol 2021;9:847-875).

AGT-2

• Bottom pathway removed: Primary aldosteronism, suspect malignant → Open adrenalectomy.
• Footnote removed: Suspect malignancies with irregular/inhomogeneous morphology, lipid-poor, do not wash-out, tumor >4 cm, or secretion of more than one hormone. When functional, these tumors are almost always associated with hypercortisolemia (± Cushing's syndrome) and often there can be multiple hormones.

AGT-3

• Second column, bottom pathway revised: Tumor >≥4 cm or inhomogeneous. . .
• Additional Evaluation column, second bullet: New sub-bullet added to second tertiary bullet: Consider additional imaging.
• New footnote k added: Depending on HU and imaging characteristics, additional imaging and workup may be indicated. Fassnacht M, et al. Eur J Endocrinol 2023;189:G1-G42.
• Footnote removed and added as a link to the algorithm: Principles of Imaging. (Also pages AGT-4 and AGT-5).

AGT-4

• Additional Evaluation:
  • New bullet added: Biochemical evaluation for hypercortisolemia (± Cushing syndrome), primary aldosteronism, and androgen excess (NE-E 2 of 4)
  • Bullets removed:
    • Fasting blood glucose
    • Serum potassium, cortisol, adrenocorticotropic hormone (ACTH)
    • 1 mg overnight dexamethasone suppression test
    • 24-hour urinary free cortisol
    • Adrenal androgens (dehydroepiandrosterone sulfate [DHEAS], androstenedione, testosterone, 17-hydroxyprogesterone)
    • Aldosterone and renin

AGT-5

• Footnotes removed and added as links in the algorithm:
  • Principles of Hereditary Cancer Risk Assessment and Genetic Counseling.
  • Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases.
• Footnote removed: Staging workup, see AGT-4.

Pheochromocytoma/Paraganglioma

PHEO-1

• Evaluation column:
  • Recommended, second bullet revised: Adrenal protocol: CT or MRI if not already done (AGT-1)
    • Sub-bullet removed: Non-contrast CT
      • Tertiary bullets removed:
        • (If HU < +10, no further imaging)
        • If > +10 HU, proceed with contrast CT with washout
• Footnotes revised:
  • Footnote a: Principles of Pathology for the Diagnosis and Reporting of Neuroendocrine Tumors Pheochromocytoma/Paraganglioma (NE-AC).
  • Footnote e: Both catecholamines and metanephrines/normetanephrines can represent false-positive results (NE-C). (Also page PHEO-3)
  • Footnote h: SSTR-PET/CT or SSTR-PET/MRI of skull base vertex to mid-thigh with multiphase IV contrast when possible. (Also page PHEO-3)

PHEO-1 (continued)

• Footnotes removed and added as links in the algorithm:
  • Principles of Biochemical Testing. (Also page PHEO-3)
  • Principles of Hereditary Cancer Risk Assessment and Genetic Counseling.
  • Principles of Imaging.
• Footnote removed: If unenhanced is < +10 HU, then the tumor is probably benign. If unenhanced is > +10 HU, then use enhanced and washout. If >60% absolute washout in 15 minutes, the tumor is likely to be benign; if <60%, the tumor is possibly malignant (Caoili EM, et al. Radiology 2002;222:629-633).

PHEO-2

• New column header added to far right of page: Surveillance.
• Primary First-Line Treatment column, removed all systemic therapy recommendations and added a new bullet: Systemic therapy (NE-H 7 of 9).
• New footnotes added:
  • Footnote k: Avoid medications that will precipitate hormone-mediated crisis.
  • Footnote l: If the patient has a hypertensive crisis, consider addition of nitroprusside, phentolamine, or nicardipine for treatment of hypertension. Cardiac arrhythmias can be managed with esmolol or lidocaine. Hypoglycemia and hypotension can be seen post-op. Treat with IV fluids for volume expansion and include dextrose for glucose levels.
• Footnote n revised: Alpha blockade is first-line therapy necessary treatment for all hormonally secreting PCCs and PGLs regardless of clinical symptoms. If additional treatments are planned, patients may need medication adjustments.
• Footnote removed and added as a link in the algorithm: Principles of Radiation Therapy.

PHEO-3

• Surveillance column following Locally unresectable disease or Distant metastases, second bullet:
  • Fourth sub-bullet revised: FDG-PET/CT for bone-dominant disease (NE-D).
  • Fifth sub-bullet revised: SSTR-PET/CT or SSTR-PET/MRI (if previous SSTR-positive or concern for disease progression) prior to considering radionuclide therapy (NE-D).

Multiple Endocrine Neoplasia, Type 1

MEN1-1

• New column header added to far right of page: Surveillance
• Footnote d revised: SSTR-PET/CT or SSTR-PET/MRI of skull base vertex to mid-thigh with multiphase IV contrast when possible. . .
• New footnote c added: Multiphasic imaging studies are performed with IV contrast in arterial and portal venous phases.
• Footnotes removed and added as links in the algorithm:
  • Principles of Hereditary Cancer Risk Assessment and Genetic Counseling.
  • Principles of Imaging. (Also page MEN1-2)

MEN1-A

• Second bullet revised: However, one notable exception is the multifocality of pancreaticoduodenal NETs in patients with MEN1. . .

Multiple Endocrine Neoplasia, Type 2

MEN2-1

• Clinical Evaluation column, bottom options:
  • Link to NE-C added.
  • First bullet revised: Plasma free or 24-hour urine fractionated metanephrines and normetanephrines ± serum or 24-hour urine catecholamines.
  • New bullet added: Biochemical evaluation as clinically indicated.
• Footnotes revised:
  • Footnote a: Removed See Principles of Imaging and added link in the algorithm.
  • Footnote g: Both catecholamines and metanephrines/normetanephrines can represent false-positive results (NE-C).
• Footnotes removed and added as links in the algorithm:
  • Principles of Hereditary Cancer Risk Assessment and Genetic Counseling.
  • Principles of Biochemical Testing.

NE-A

• Principles of Pathology for the Diagnosis of Neuroendocrine Neoplasms: Significant changes have been made to this section.

NE-B

• New Principles of Pathology for the Diagnosis of Adrenocortical Carcinoma.

NE-C

• New Principles of Pathology for the Diagnosis of Pheochromocytoma/Paraganglioma.

NE-D 1 of 3

• Anatomic Imaging:
  • Second bullet revised: The liver is a common metastatic site for NET, and these metastatic lesions are often hypervascular. Therefore, multiphasic imaging should be performed whenever possible. Following arterial-phase imaging of the liver, imaging of the abdomen and pelvis can be performed in the portal-venous phase of enhancement. Oral contrast may be helpful to delineate discrete lesions within the bowel. Multiphase (dual-phase) contrast-enhanced (arterial and portal venous phase) CT is important because NETs frequently enhance in the arterial phase. SSTR-PET/CT should be interpreted in combination with dual-phase CT or MRI to identify both SSTR(+) and SSTR(-) sites of disease. PET/CT and PET/MRI scanners are capable of providing full diagnostic multiphase contrast-enhanced CT and MRI scans. This provides the most accurate correlation of anatomic sites and receptor status. When possible, SSTR-PET/CT and SSTR-PET/MR should be performed concurrently with diagnostic multiphase CT or MRI.
  • Third bullet revised: Without a known tumor or specific clinical concern, imaging of the chest is optional for GI NET should include chest CT ± contrast and imaging of the brain is generally not required for well-differentiated NET.
• Functional Imaging, new bullet added: Combining FDG-PET and SSTR-PET, even for lower grade tumors, and a combined score of FDG-PET and SSTR-PET gives more prognostic value and outperforms pathological grading.

NE-D 2 of 3

• Transthoracic Echocardiogram to Assess for Carcinoid (NET-related) Heart Disease:
  • First bullet revised: Transthoracic echocardiogram (transthoracic echocardiographyTTE) is important for the evaluation of CHD and should include morphologic evaluation of the valves (especially tricuspid and pulmonic pulmonary), as well as assessment of and the right heart size and function. When valve disease is present, an agitated saline injection should be performed to determine whether there is an atrial level shunt.
  • New bullet added: Post valve replacement, patients should be followed with serial echocardiograms according to institutional practice. If valves are abnormal by echocardiogram, consider the potential for clots requiring resumption of anticoagulants versus recurrent CHD.
  • New table added: Repeat TTE Recommendations for Patients with NETs:
    • Without known CHD:
      • Symptoms of dyspnea, fatigue, edema, or ascites.
      • Physical exam findings including elevated jugular venous pressure, edema, or ascites.
      • Prior to planned bowel/liver resection.
      • Reassessment every 1–3 years.
    • Known CHD with or without prior valve surgery:
      • Decision-making in conjunction with a multidisciplinary care team.
      • Annual reassessment of all valves (native ± prosthetic) in conjunction with specialty cardiology consultation.
      • New symptoms of dyspnea, fatigue, edema, or ascites.
      • Change in physical exam including elevated jugular venous pressure, edema, or ascites.
      • Prior to planned bowel/liver resection.

NE-D 3 of 3

• New reference added: Hope TA, Allen-Auerbach M, Bodei L, et al. SNMMI procedure standard/EANM Practice Guideline for SSTR PET: Imaging neuroendocrine tumors. J Nucl Med 2023;64:204-210.

NE-E 1 of 4

• Testing column for Insulinoma:
  • New bullet added: Fasting blood glucose.
  • Third bullet revised: See Workup Evaluation for insulinoma (PanNET-5).

NE-E 2 of 4

• Testing column for Suspected or confirmed ACC:
  • New bullet added: Screen for hypercortisolemia (± Cushing syndrome) and primary aldosteronism.
  • Bullets removed:
    • Fasting blood glucose.
    • Serum potassium, cortisol, ACTH.
    • 1 mg overnight dexamethasone suppression test.
    • 24-hour urinary free cortisol.
    • Aldosterone and renin.

NE-E 3 of 4

• Footnote b, removed reference: Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014;99:1915-1942.

NE-E 4 of 4

• Reference removed: Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014;99:1915-1942.

NE-F 1 of 3

• First bullet revised: Standard oncologic surgery (eg, distal pancreatectomy/splenectomy or pancreaticoduodenectomy) is appropriate for most resectable, nonmetastatic PanNETs. . .
• Fourth bullet revised: Resection of GI NETs should include adequate regional lymph node resection (including all palpable disease where feasible). This is especially important for small bowel NETs were manual palpation of the entire length of bowel is recommended as the rate and thorough exploration of synchronous primary tumors is high (15%–30% incidence). Resection of palpated lesions can be performed using a hybrid minimally invasive approach, if feasible.
• New bullet added: Surgical resection of lung tumors is recommended for localized and resectable locoregional disease. There are no randomized data regarding extent of surgical resection but retrospective analyses suggest that if the tumor can be resected completely, a sublobar resection may yield outcomes similar to a lobectomy even for atypical carcinoids.

NE-F 2 of 3

• Second bullet revised: Cholecystectomy is recommended when performing surgery for advanced NETs in patients anticipated to receive long-term octreotide LAR therapy SSAs, as these patients are at higher risk of developing biliary symptoms and cholecystitis.

NE-F 3 of 3

• New references added:
  • Ernani V, Appiah AK, Rodriguez D, et al. Lobar versus sublobar resection for atypical lung carcinoid: An analysis from the National Cancer Database. Cancer 2023;129:860-866.
  • Maxwell JE, Naraev B, Halperin DM, Choti MA, Halfdanarson TR. Shifting paradigms in the pathophysiology and treatment of carcinoid crisis. Ann Surg Oncol 2022;29:3072-3084.

NE-G 2 of 8

• 2) Considerations When Determining the Most Appropriate Testing Strategy, first bullet revised: The introduction of multigene testing for hereditary cancer/ tumor predisposition endocrine neoplasia syndromes has rapidly altered the clinical approach to genetic testing of at-risk patientsand their families.
• 3) Post-Test Counseling Includes the Following Elements: fourth bullet, second sub-bullet revised: Discussion of the importance of notifying family members and offering materials/resources for information and testing at-risk of family members.

NE-H 1 of 9

• First bullet revised: Systemic therapy may not be appropriate for every patient with locoregionally advanced and/or distant metastatic disease. Consider multidisciplinary discussion to determine the best choice of treatment, including: observation for patients with stable disease with mild tumor burden, liver-directed therapy for patients with liver-predominant disease locoregional therapy, cytoreductive surgery, or systemic therapy, which may be appropriate considerations.
• First column of table revised: Locoregional Advanced Disease and/or Distant Metastases (if clinically or radiologically significant disease progression on octreotide LAR or lanreotide).
• Preferred Regimens:
  • First bullet revised: Everolimus (category 1 for nonfunctional tumors).
  • New bullet added: Octreotide LAR or lanreotide.
• New footnotes added:
  • Footnote c: Phase III study done in nonfunctional tumors. (Also page NE-H 2 of 9)
  • Footnote d: Treatment with octreotide LAR or lanreotide will likely be of greatest benefit in patients with SSTR-positive tumors.
• Footnotes removed and added as links in the table:
  • Principles of Peptide Receptor Radionuclide Therapy with Lutetium Lu 177 Dotatate. (Also pages NE-H 2 of 9 and NE-H 3 of 9)
  • Principles of Radiation Therapy. (Also pages NE-H 3 of 9 and NE-H 4 of 9)

NE-H 2 of 9

• First bullet revised: Systemic therapy may not be appropriate for every patient with distant metastatic disease. Consider multidisciplinary discussion to determine the best choice of treatment, including: observation for patients with stable disease with mild tumor burden, liver-directed therapy for patients with liver-predominant disease locoregional therapy, cytoreductive surgery, or systemic therapy, which may be appropriate considerations.
• Preferred Regimens:
  • First bullet revised: Everolimus (category 1 for bronchopulmonary nonfunctional lung NETs).
  • Bullet removed: Clinical Trial.
• New footnote i added: For patients with insulinoma, octreotide LAR or lanreotide should be used only if SSTR-based imaging is positive. If used, they should be used with caution in patients with insulinoma as they may transiently worsen hypoglycemia (see Discussion for details).

NE-H 3 of 9

• First bullet revised: Systemic therapy may not be appropriate for every patient with locoregionally advanced and/or distant metastatic disease. Consider multidisciplinary discussion to determine the best choice of treatment, including: observation for patients with stable disease with mild tumor burden, liver-directed therapy for patients with liver-predominant disease locoregional therapy, cytoreductive surgery, or systemic therapy.
• Fifth bullet revised: For management of hormone-related symptoms and complications with octreotide or lanreotide, see PanNET-1 through PanNET-10.
• Useful in Certain Circumstances, new bullet added: Octreotide LAR or lanreotide (if SSTR-negative).
• New footnote k added: For patients with insulinoma, octreotide LAR or lanreotide should be used only if SSTR-based imaging is positive. If used, they should be used with caution in patients with insulinoma as they may transiently worsen hypoglycemia (see Discussion for details).

NE-H 4 of 9

• Locoregional Disease (Resectable with Unfavorable Biology), second bullet revised: Neoadjuvant chemotherapy on a case-by-case basis (eg, Ki-67 >≥55%).
• Footnote p revised: Consider trial of SSA before PRRT. Preliminary data suggest reduced efficacy if high Ki-67 and/or FDG-PET avid. See Principles of Peptide Receptor Radionuclide Therapy with Lutetium Lu 177 Dotatate (NE-H).

NE-H 7 of 9

• Locally Unresectable, fifth bullet revised: Consider PRRT with lutetium Lu 177 dotatate (if SSTR-positive) (NE-J).
• Distant Metastases, fifth bullet revised: Consider PRRT with lutetium Lu 177 dotatate (if SSTR-positive) (NE-J).
• Footnote z revised: Data are limited on the use of PRRT with lutetium Lu 177 dotatate in this setting. See Principles of Peptide Receptor Radionuclide Therapy with Lutetium Lu 177 Dotatate (NE-H).

NE-H 8 of 9

• New reference 21 added: Refardt J, Zandee WT, Brander T, et al. Inferior outcome of neuroendocrine tumor patients negative on somatostatin receptor imaging. Endocr Relat Cancer 2020;27:615-624.

NE-H 9 of 9

• New references added:
  • Reference 44: Jaiswal SK, Sarathi V, Memon SS, et al. 177Lu-DOTATATE therapy in metastatic/inoperable pheochromocytoma-paraganglioma. Endocr Connect 2020;9:864-873.
  • Reference 45: Vyakaranam AR, Crona J, Norlén O, et al. Favorable outcome in patients with pheochromocytoma and paraganglioma treated with 177Lu-DOTATATE. Cancers (Basel) 2019;11:909.

NE-I 1 of 2

• Locoregional Disease:
  • Second bullet revised: Specific sites where EBRT may be considered include lung, thymus, and in locations in the GI tract where resection may be associated with significant morbidity, such as esophagus, stomach, pancreas, or rectum. Depending on disease site, treatment may be adjuvant (postoperative), definitive, or palliative. For details on techniques, please refer to the appropriate NCCN Guidelines for the respective primary cancer types.
  • Third bullet revised: EBRT generally does not play a role in the management of locoregional NETs of the small bowel, appendix, or colon (including mesenteric disease), due to risk of bowel injury. However, focal EBRT may be considered in select circumstances using conformal techniques and careful attention to bowel dose constraints.

NE-J 1 of 3

• Top of the page, second bullet revised: It is approved by the FDA for the treatment of adult and pediatric patients ≥12 years of age with SSTR-positive GEP NETs, including foregut, midgut, and hindgut NETs in adults.
• Footnote a revised: SSTR-PET/CT or SSTR-PET/MRI of skull base vertex to mid-thigh with multiphase IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.
• Footnote removed and added as a link in the algorithm: Principles of Imaging (NE-B).Please note: Principles of Imaging can now be found on NE-D.

NE-J 2 of 3

• Dose and Administration:
  • First bullet revised: Lutetium Lu 177 dotatate is administered intravenously (IV) via peripheral IV at a dose of 200 mCi over 30–40 minutes every 8 weeks for a total of 4 treatments (unless dose modification required secondary to adverse reactions).
  • Third bullet revised: Antiemetic medications should be available prior to and during amino acid and lutetium Lu 177 dotatate infusions. Aggressive antiemetic prophylaxis is recommended for patients when nonselective amino acid solutions are used with PRRT. Routine prophylactic antiemetics may not be necessary if selective (arginine/lysine) amino acid solutions are used, but should be available as needed.

NE-J 3 of 3

• Reference 1 revised: National Institutes of Health. Lutetium Lu 177 dotatate package insert. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72d1a024-00b7-418ab36e-b2cb48f2ab55. Accessed April 13, 2021. Prescribing information for lutetium Lu 177 dotatate injection, for intravenous use. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208700s031lbl.pdf. Accessed June 18, 2024.

NE-K 1 of 2

• Indications for Hepatic Arterial Embolization, third bullet revised: Relative contraindications include significant baseline liver dysfunction (eg, jaundice, ascites) and a liver tumor burden >70%. . .

NE-L 1 of 3

• Carcinoid Syndrome:
  • New bullets added:
    • Carcinoid crisis is a potentially life-threatening form of carcinoid syndrome caused by a massive release of vasoactive substances, often triggered by tumor manipulation or anesthesia. It is typically associated with hypotension, diarrhea, and blood pressure fluctuation.
      • New sub-bullet added: The prevalence and risk of carcinoid crisis varies greatly across studies according to the diagnostic criteria used.
    • Octreotide should be available as needed during surgical procedures for patients with carcinoid syndrome who develop hemodynamic instability that could indicate carcinoid crisis. Doses of octreotide (100–500 mcg IV) can be used, potentially followed by IV infusion of octreotide (50–300 mcg/h).
    • Vasopressors can be used for severe and/or prolonged hypotension.
    • Prophylactic administration of octreotide prior to surgery can be utilized although intraoperative complications can still arise, and the
    • routine use of prophylactic octreotide has been called into question.
• New references added:
  • Reference 1: Maxwell JE, Naraev B, Halperin DM, Choti MA, Halfdanarson TR. Shifting paradigms in the pathophysiology and treatment of carcinoid crisis. Ann Surg Oncol 2022;29:3072-3084.
  • Reference 2: Howe JR, Cardona K, Fraker DL, et al. The surgical management of small bowel neuroendocrine tumors: Consensus Guidelines of the North American Neuroendocrine Tumor Society. Pancreas 2017;46:715-731.
  • Reference 3: McCully BH, Kozuma K, Pommier S, Pommier RF. Comparison of octreotide and vasopressors as first-line treatment for intraoperative carcinoid crisis. Ann Surg Oncol 2024;31:2996-3002.
  • Reference 4: Kaltsas G, Caplin M, Davies P, et al. ENETS Consensus Guidelines for the standards of care in neuroendocrine tumors: Pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology 2017;105:245-254.
  • Reference 5: Wonn SM, Ratzlaff AN, Pommier SJ, McCully BH, Pommier RF. A prospective study of carcinoid crisis with no perioperative octreotide. Surgery 2022;171:88-93.

NE-L 2 of 3

• Table heading revised: Symptom Management of Carcinoid Syndrome.

ST-1

• Staging table for Well-Differentiated Neuroendocrine Tumors of the Jejunum and Ileum (small bowel [NET G1, and G2, and rare well-differentiated G3] arising in the jejunum and ileum) was updated to Version 9, 2023.

ST-2

• Staging table for Well-Differentiated Neuroendocrine Tumors of the Duodenum and Ampulla of Vater (NET G1, G2, and G3) was updated to Version 9, 2023.

ST-3

• Staging table for Well-Differentiated Neuroendocrine Tumors of the Appendix [(NET G1, and G2, and rare well-differentiated G3]) was updated to Version 9, 2023.

ST-4

• Staging table for Well-Differentiated Neuroendocrine Tumors of the Colon and Rectum [neuroendocrine tumor (NET G1, and G2, and rare well-differentiated G3]) was updated to Version 9, 2023.

ST-5

• Staging table for Well-Differentiated Neuroendocrine Tumors of the Stomach (NET G1, and G2, and rare well-differentiated G3) was updated to Version 9, 2023.

ST-9

• Staging table for Well-Differentiated Neuroendocrine Tumors of the Pancreas [well-differentiated neuroendocrine tumors arising in the pancreas] (NET G1, G2, and G3) was updated to Version 9, 2023.

ST-10

• New Staging table for Adrenal Cortical Carcinoma (8th ed., 2017) was added.

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